B cell-Derived IL35 Drives STAT3-Dependent CD8+ T-cell Exclusion in Pancreatic Cancer

Cancer Immunol Res. 2020 Mar;8(3):292-308. doi: 10.1158/2326-6066.CIR-19-0349. Epub 2020 Feb 5.


Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy characterized by a paucity of tumor-proximal CD8+ T cells and resistance to immunotherapeutic interventions. Cancer-associated mechanisms that elicit CD8+ T-cell exclusion and resistance to immunotherapy are not well-known. Here, using a Kras- and p53-driven model of PDA, we describe a mechanism of action for the protumorigenic cytokine IL35 through STAT3 activation in CD8+ T cells. Distinct from its action on CD4+ T cells, IL35 signaling in gp130+CD8+ T cells activated the transcription factor STAT3, which antagonized intratumoral infiltration and effector function of CD8+ T cells via suppression of CXCR3, CCR5, and IFNγ expression. Inhibition of STAT3 signaling in tumor-educated CD8+ T cells improved PDA growth control upon adoptive transfer to tumor-bearing mice. We showed that activation of STAT3 in CD8+ T cells was driven by B cell- but not regulatory T cell-specific production of IL35. We also demonstrated that B cell-specific deletion of IL35 facilitated CD8+ T-cell activation independently of effector or regulatory CD4+ T cells and was sufficient to phenocopy therapeutic anti-IL35 blockade in overcoming resistance to anti-PD-1 immunotherapy. Finally, we identified a circulating IL35+ B-cell subset in patients with PDA and demonstrated that the presence of IL35+ cells predicted increased occurrence of phosphorylated (p)Stat3+CXCR3-CD8+ T cells in tumors and inversely correlated with a cytotoxic T-cell signature in patients. Together, these data identified B cell-mediated IL35/gp130/STAT3 signaling as an important direct link to CD8+ T-cell exclusion and immunotherapy resistance in PDA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • B-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology*
  • Carcinoma, Pancreatic Ductal / pathology
  • Carcinoma, Pancreatic Ductal / therapy
  • Case-Control Studies
  • Cell Proliferation / physiology
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interleukins / genetics
  • Interleukins / immunology*
  • Lymphocyte Activation
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / immunology
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Regulatory / immunology
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • CCR5 protein, human
  • CCR5 protein, mouse
  • CXCR3 protein, human
  • Cxcr3 protein, mouse
  • Interleukins
  • Receptors, CCR5
  • Receptors, CXCR3
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • interleukin-35, human
  • interleukin-35, mouse